Miller Michelle S, Mountford Simon J, Pinson Jo-Anne, Zheng Zhaohua, Künzli Marco, Patel Vanit, Hogg Simon J, Shortt Jake, Jennings Ian G, Thompson Philip E
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
Bioorg Med Chem Lett. 2016 Oct 1;26(19):4790-4794. doi: 10.1016/j.bmcl.2016.08.028. Epub 2016 Aug 11.
A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of 'on-target' activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.
制备了一系列源自泛PI3K抑制剂ZSTK474的PI3Kδ抑制剂，这些抑制剂靶向催化位点的一个非保守区域。根据存在的取代基不同，这些类似物对PI3Kδ中的N836D突变表现出不同水平的亚型选择性和敏感性。作为“靶向”活性和通透性的标志物，一些最有效的PI3Kδ抑制剂被证明能抑制纳瓦尔马伯基特淋巴瘤细胞系中pAkt的产生。
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